Gonadotropin releasing hormone (GnRH) is a key regulator of reproductive functions. Repeated administration of potent and long acting GnRH agonists inhibits gonadal functions through desensitization of the GnRH receptor. This property is used clinically for t he treatment of prostate cancers, managed of endometriosis and in vitro fertilization for example. Potent peptide antagonists of GnRH have also been identified recently that have the advantage of intermediate and more profound inhibition of gonadotropins than the agonists thus opening the door to the use of the former for male contraception. None of these peptides are potent orally, Peptide GnRH agonists and antagonists are very different structurally. Whereas nothing is known of the conformation of GnRH agonists at the receptor, we have shown that several covalent constraints [cyclo(4-10), cyclo(5-8) and cyclo(1-5)] in GnRH antagonists are compatible with high affinity and in vivo potency. The NMR structures of these analogs led to the determination of a GnRH antagonist consensus model that was used for the successful design of a bioactive tri-aminoglycine-based library. Additionally, this model was helpful in identifying a putative one-to-one correspondence with elements of a potent non-peptide ligand (T-98475). We have also successfully introduced urea function in several GnRH antagonist structures that resulted in high affinity and extended duration of action, suggesting an important role for inter/intramolecular hydrogen bonding interactions in peptide stability, solubility and distribution. One the basis of these results, we propose to test four hypotheses: A. Strategically placed positive and negative charges on residues (1-5), (4-10) and (5-8) will stabilize the GnRH bioactive conformation with retention of biological activity, B. The GnRH antagonist consensus model will be used for the design of small GnRH peptidomimetic ligands containing aminoglycine scaffolds (betide), C. Functional groups found in GnRH rather than in GnRH antagonists will be introduces in betides to field the first peptidomimetic GnRH agonist and structural insights on the process of receptor activation, D. Optimization of hydrogen bonding interactions using urea functionalities will yield safe and long activating GnRH antagonists that display immediate onset of action in short- and long-term indications. Such molecules are not presently available to academic researchers. As in the past twenty years, collaborations with academic colleagues will be initiated, to maximize the impact of this research.